What is Helicobacter pylori?
Helicobacter pylori, a common pathogen associated with the peptic ulcers (ulcers in the stomach and upper small intestine) is one of the most common pathogens affecting humankind, infecting approximately 50% of the world’s population. This pathogen is a gram-negative spiral shaped bacterium that has the unique ability to colonize the human gastric mucosa. The infection is usually acquired early in life and may persist a lifetime, unless treated. Of those infected, many will develop asymptomatic gastritis, but 10% develop gastric or duodenal ulcers, and approximately 1% develop gastric carcinoma. The outcome of the infection may involve a combination of the bacterial factors, host factors, as well as environmental factors. Ulceration and carcinogenesis are mutually exclusive outcomes of this infection. H. pylori infection is a very persistent infection, and in areas of high prevalence, reinfection is also very common. H. pylori infection is common, especially in low- and middle-income countries. The Centers for Disease Control and Prevention estimates that approximately two-thirds of the global population carries the bacterium.
A very high percentage of gastric and duodenal ulcers (up to 85%) are attributable to H. pylori infection. Patients in the United States who are infected with H. pylori have a 3.5 times increased risk of developing peptic ulcer disease than uninfected persons. A hallmark feature of infection with H. pylori is a pronounced inflammatory response and the inability of the host to clear the infection, which results in a persistent infection, increased acid production, and tissue damage.
The infection is primarily spread through oral contact with feces (feco–oral route), saliva (oral–oral), or vomit (gastric–oral). It is typically acquired during childhood, particularly in children from impoverished backgrounds, crowded conditions, or areas with poor sanitation. H. pylori is probably the most prevalent human pathogen worldwide and is implicated in gastritis and peptic ulcer disease. It is now well accepted that chronic infection with H. pylori is a major risk factor in the development of gastric cancer and was classified as a class I carcinogen by the International Agency for Research on Cancer in affiliation with the World Health Organization. Most infections are acquired early in life and may persist for the life of the individual. H. pylori has been shown to induce changes in the gastric mucosa that could contribute to the development of cancer.
Gastric cancer remains the second deadliest cancer worldwide. On a global scale, gastric cancer accounts for approximately 700 000 deaths annually. In the US there are 24 000 new cases and 14 000 deaths annually. It has been shown that risk factors for gastric cancer development are high-salt and meat-rich diets, alcohol consumption, cigarette smoke, but also family history and gastro-oesophageal reflux. Notwithstanding the importance of these risk factors, Helicobacter pylori infection is still considered the main risk factor for stomach cancer initiation. Although there has been a remarkable decrease of H. pylori infection during the last decade, more than half of the world population is still affected, but not all patients develop symptoms and only 1–3% of H. pylori-infected patients develop gastric cancer. Symptoms might depend on the virulence of specific strains, host genetic factors and diet. Interestingly, more recent evidence suggests that the disease starts when the bacterium colonizes deep in the gastric mucosal barrier. Despite the acidic environment, H. pylori can survive by neutralizing the local acidity around it, though not the entire stomach. It also burrows into the mucus layer and attaches to the stomach lining, evading immune response since immune cells cannot reach the bacteria. Additionally, H. pylori interferes with the immune system, making it difficult for the body to eliminate the infection.
Mechanism of pathogenesis
The gut mucosa is organized in narrow invaginations called glands that are made of a simple columnar epithelium. The content of the gut lumen is never in contact with the inner part of the gland, however, H. pylori has evolved strategies to penetrate inside to establish a protected niche where the infection can persist. The epithelial barrier is the first to reacts against the infectious agent. Pathogenic bacteria like H. pylori have evolved strategies to break this first line of defense and adhere to the gastric epithelium by harnessing specific host cell receptors. While inducing a strong inflammatory response, H. pylori is also able to evade the immune system and to cause profound changes in tissue morphology as a response to the damage caused by the infection. While infected individuals mount an inflammatory response that becomes chronic, along with a detectable adaptive immune response, these responses are ineffective in clearing the infection. H pylori has unique features that allow it to reside within the harsh conditions of the gastric environment, and also to evade the host immune response. H. pylori infection induces indeed genomic instability into the infected cells posing them at risk of somatic mutation.
Infection with H pylori also plays a critical role in the development of mucosa-associated lymphoid tissue (MALT) lymphoma. H pylori is present in the gastric mucosa of most cases of MALT lymphoma, and 75% of these cases regress after eradication of H pylori. Interestingly, gastric MALT lymphoma is the only known malignancy whose course can be directly changed by the removal of a pathogen. Thus, H pylori-associated diseases are a significant global problem and result in considerable morbidity, mortality, and societal costs.
In 1994, the World Health Organization’s International Agency for Research on Cancer classified H. pylori as a human carcinogen. Furthermore, the 15th Report on Carcinogens by the National Toxicology Program in 2021 confirmed chronic H. pylori infection as a known or reasonably anticipated cause of cancer in humans.
H. pylori’s Role in Stomach Cancer?
There is substantial evidence linking chronic H. pylori infection with gastric adenocarcinoma and gastric MALT lymphoma:
- Gastric Adenocarcinoma: Numerous studies show that individuals with chronic H. pylori infections have a higher risk of developing gastric adenocarcinoma in the main part of the stomach and gastric cancer Eradicating H. pylori reduces the risk of gastric cancer, particularly in asymptomatic individuals, those with a family history, and those who have had surgery for early gastric cancer.
- Gastric MALT Lymphoma: Almost all patients with gastric mucosa-associated lymphoid tissue lymphoma exhibit signs of H. pylori infection. Eradication of H. pylori using antibiotics has been shown to shrink tumors in these patients.
Factors That Increase the Likelihood H. pylori Infections Will Be Harmful
Several factors increase the risk of H. pylori infections leading to cancer, including:
- Toxins: Some H. pylori strains produce a toxin called CagA, which can cause stomach cells to become cancerous by disrupting their growth controls and promoting inflammation. Strains that produce CagA are more strongly linked to gastric cancer.
- Lifestyle Factors: Smoking, high salt intake, and processed meat consumption can increase the risk of stomach cancer in H. pylori-infected individuals, possibly by enhancing bacterial colonization or promoting toxin entry into stomach cells.
Eradicating H. pylori infection significantly reduces the risk of gastric cancer. A clinical trial in China found that 2 weeks of antibiotic treatment halved the incidence of gastric cancer over 22 years.
Stages Crucial for the Development of Gastric Cancer
To understand how H. pylori infection can lead to gastric cancer, researchers utilize various models that study the progression of the infection through four key stages: colonization of the gastric mucosa by H. pylori, inflammation and immune evasion by the bacteria, disruption of epithelial homeostasis within the stomach lining, and ultimately, DNA damage which can trigger carcinogenic transformation within the epithelial cells; each stage is crucial for the development of gastric cancer associated with H. pylori infection.
- Colonization: H. pylori possesses specific adhesion proteins such as adhesins on its surface which allow it to firmly attach to the gastric epithelial cells, facilitating colonization in the stomach lining, primarily in the antrum region. The bacteria can penetrate the mucus layer of the stomach, allowing close contact with the epithelial cells. H. pylori produces urease, an enzyme that breaks down urea into ammonia, creating a more alkaline microenvironment around the bacteria which helps them survive in the acidic stomach.
- Inflammation and Immune Evasion: Upon colonization, H. pylori triggers an inflammatory response by stimulating the release of pro-inflammatory cytokines like IL-8 and TNF-alpha from immune cells, leading to infiltration of immune cells into the gastric mucosa. H. pylori can manipulate the immune response by suppressing the activity of immune cells like dendritic cells, hindering their ability to effectively present antigens to T cells and promoting immune tolerance. H. pylori can undergo variations in its surface proteins, allowing it to evade the host immune system by constantly presenting new targets.
- Disruption of Epithelial Homeostasis: H. pylori infection can lead to increased cell proliferation within the gastric epithelium, disrupting the normal cell turnover rate. Certain bacterial factors can disrupt the tight junctions between epithelial cells, increasing permeability and allowing harmful substances to leak into the underlying tissue. H. pylori can induce programmed cell death (apoptosis) in gastric epithelial cells, contributing to epithelial barrier disruption.
- DNA Damage: The inflammatory response triggered by H. pylori can generate reactive oxygen species which can damage DNA. H. pylori can also directly damage DNA through the production of genotoxic substances or by interfering with DNA repair mechanisms. H. pylori infection can lead to epigenetic modifications in the host genome, altering gene expression and potentially promoting oncogenesis.
Inflammation and Virulence Factors associated with H. pylori pathogenesis:
Inflammation is a central feature of H. pylori pathogenesis, triggered by both antigen-specific and non-specific immune responses. These immune responses, while fighting the infection, also contribute to tissue damage. Bacterial factors such as urease stimulate proinflammatory cytokine and chemokine production.
Impact of H. pylori on the Gastric Epithelium
Enhanced Cell Turnover and Apoptosis
One of the responses of gastric epithelial cells to H. pylori infection is enhanced proliferation. To maintain a balance with the increased cell growth, the host compensates with increased cell turnover, a process that includes apoptosis. In the gastrointestinal tract, apoptosis is crucial for regulating normal epithelial cell turnover and is elevated in the gastric epithelium during H. pylori infection. The induction of apoptosis may be influenced by cytokines and growth factors such as IFN-γ, which not only enhances H. pylori‘s ability to induce apoptosis but also increases the expression of receptors that facilitate bacterial attachment.
ROS and DNA Damage
Reactive oxygen species produced by neutrophils and gastric epithelial cells in response to H. pylori infection play a significant role in DNA damage. Although H. pylori is resistant to the antimicrobial effects of reactive oxygen species, these reactive molecules can cause DNA damage in the gastric epithelium, potentially leading to pro-carcinogenic events. The extent of reactive oxygen species production is correlated with bacterial load; higher bacterial loads result in greater reactive oxygen species production, causing more significant epithelial damage. Low bacterial loads may disrupt the balance between oxidants and antioxidants, raising the risk of DNA damage and subsequent carcinogenesis.
Who Should Be Tested and Treated for H. pylori Infection?
The CDC recommends testing and treatment for H. pylori in individuals with active gastric or duodenal ulcers or a history of ulcers. It is also recommended for those who have had surgery for early gastric cancer or low-grade gastric MALT lymphoma. However, widespread testing and eradication are not universally recommended, as unnecessary treatment could contribute to increased antibiotic resistance in the U.S.
